Despite significant investment in recent years, robust medical countermeasures to address the NIAID Category A, B, and C priority agents remain scarce. In addition to the threat posed by bacteria that can be used as bioweapons, the increasing incidence of multidrug-resistance among gram-positive and gram-negative pathogens has raised many concerns, due to the limited number of marketed antibiotics with activity against these pathogens and a dearth of new antibiotics that will provide coverage in the drug development pipeline. In addition to the alarming levels of resistance among traditional bacterial public health threats, the possibility for priority agents to acquire resistance to current therapies either naturally or via engineering is a serious threat. Consequently, a broad-spectrum antibiotic with activity against multiple susceptible and drug-resistant biothreat pathogens would be a valued addition to the armamentarium for empiric treatment during an aerosolized attack and for protective prophylaxis. Multidrug-resistant microbes are considered a substantial threat to US public health and national security. The proposed studies are aimed at advancing TP-271 toward clinical development for the treatment of respiratory infections caused by susceptible and drug-resistant NIAID Category A, B and C biothreat and public health pathogens. Treatment and post-exposure prophylaxis against pneumonic plague - which is associated with up to 60% mortality - and CABP (such as methicillin-resistant Staphylococcus aureus) are the initially targeted indications. However, given TP-271's broad-spectrum antibacterial activity, it is expected that TP-271 will protect against many other biodefense threats. To substantiate this, the proposed work will also investigate the efficacy of TP-271 against Francisella tularensis in mice. Once licensure by the FDA ultimately occurs, the intention is to continue to build a clinical safety database and expand the approval of TP-271 for other serious respiratory infections, including additional Category A and B pathogens such as F. tularensis. To support the development of TP-271 toward IND, a preclinical plan has been proposed which 1) evaluates oral bioavailability in chimpanzees; 2) demonstrates efficacy in a mouse model of pneumonic plague and optimizes dosing; 3) demonstrates efficacy in a mouse model of tularemia; 4) examines the PK/PD of TP-271 in a murine model of MRSA infection; and 5) collects GLP, IND-enabling data to support safety in multiple species and in in vitro screens.